Oxysterols and methods of use thereof

ABSTRACT

Compounds are provided according to Formula (III):and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R2, R3, R5, and n are as defined herein, and at least one hydrogen is replaced with a deuterium. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a Continuation of U.S. application Ser. No.16/099,122, filed Nov. 5, 2018, which is a U.S. National PhaseApplication under 35 U.S.C. § 371 of International ApplicationPCT/US2017/031374, filed May 5, 2017, which claims priority under 35U.S.C. § 119(e) to U.S. provisional patent application Ser. No.62/332,959, filed May 6, 2016. The entire contents of each of theforegoing applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/orNR3 subunits and possess distinct recognition sites for exogenous andendogenous ligands. These recognition sites include binding sites forglycine, and glutamate agonists and modulators. NMDA receptors areexpressed in the peripheral tissues and the CNS, where they are involvedin excitatory synaptic transmission. Activating these receptorscontributes to synaptic plasticity in some circumstances andexcitotoxicity in others. These receptors are ligand-gated ion channelsthat admit Ca2+ after binding of the glutamate and glycine, and arefundamental to excitatory neurotransmission and normal CNS function.Positive modulators may be useful as therapeutic agents with potentialclinical uses as cognitive enhancers and in the treatment of psychiatricdisorders in which glutamatergic transmission is reduced or defective(see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46),10318-10325). In contrast, negative modulators may be useful astherapeutic agents with potential clinical uses in the treatment ofpsychiatric disorders in which glutamatergic transmission ispathologically increased (e.g., treatment resistant depression).

Oxysterols are derived from cholesterol and have been shown to potentlyand selectively modulate NMDA receptor function. New and improvedoxysterols are needed that modulate the NMDA receptor for the preventionand treatment of conditions associated with NMDA expression andfunction. Compounds, compositions, and methods described herein aredirected toward this end.

SUMMARY OF THE INVENTION

Provided herein are substituted oxysterols useful for preventing and/ortreating a broad range of disorders, including, but not limited to,NMDA—mediated disorders. These compounds are expected to show improvedin vivo potency, pharmacokinetic (PK) properties, oral bioavailability,formulatability, stability, and/or safety as compared to otheroxysterols. Further provided are pharmaceutical compositions comprisingthe compounds of the present invention, and methods of their use andtreatment.

In one aspect, provided herein are compounds according to Formula (III):

or a pharmaceutically acceptable salt thereof, wherein each of R² and R³is independently hydrogen or —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl); R⁵ isabsent or hydrogen; n is 1 or 2;

represents a single or double bond, wherein when one

is a double bond, the other is a

single bond and R⁵ is absent; and at least one hydrogen is replaced witha deuterium.

In one aspect, provided herein are compounds according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen ordeuterium; each of R² and R³ is independently hydrogen, deuterium or—C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl); R⁴ is hydrogen or deuterium; R⁵ isabsent, hydrogen, or deuterium; n is 1 or 2;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and at least one of R¹, R², R³, R⁴,or R⁵ is deuterium.

In some embodiments, the compound of Formula (II) is a compound ofFormula (I):

In an aspect, provided herein is a pharmaceutical composition comprisinga compound described herein, or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

In an aspect, provided herein is a method of inducing sedation oranesthesia comprising administering to a subject an effective amount ofa compound described herein, or pharmaceutically acceptable saltthereof, or pharmaceutical composition thereof.

In an aspect, provided herein is a method for treating or preventing adisorder described herein, comprising administering to a subject in needthereof an effective amount of a compound described herein, orpharmaceutically acceptable salt thereof, or pharmaceutical compositionthereof.

In some embodiments, the disorder is a gastrointestinal (GI) disordere.g., constipation, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD) (e.g., ulcerative colitis, Crohn's disease), structuraldisorders affecting the GI, anal disorders (e.g., hemorrhoids, internalhemorrhoids, external hemorrhoids, anal fissures, perianal abscesses,anal fistula), colon polyps, cancer, colitis.

In some embodiments, the disorder is inflammatory bowel disease.

In some embodiments, the disorder is cancer, diabetes, or a sterolsynthesis disorder.

In an aspect, provided herein is a method for treating or preventing aCNS-related condition comprising administering to a subject in needthereof an effective amount of a compound described herein, orpharmaceutically acceptable salt thereof, or pharmaceutical compositionthereof. In some embodiments, the CNS-related condition is an adjustmentdisorder, anxiety disorder (including obsessive-compulsive disorder,posttraumatic stress disorder, and social phobia), cognitive disorder(including Alzheimer's disease and other forms of dementia),dissociative disorder, eating disorder, mood disorder (includingdepression (e.g., postpartum depression), bipolar disorder, dysthymicdisorder, suicidality), schizophrenia or other psychotic disorder(including schizoaffective disorder), sleep disorder (includinginsomnia), substance-related disorder, personality disorder (includingobsessive-compulsive personality disorder), autism spectrum disorders(including those involving mutations to the Shank group of proteins(e.g., Shank3)), neurodevelopmental disorder (including Rett syndrome,Tuberous Sclerosis complex), multiple sclerosis, sterol synthesisdisorders, pain (including acute and chronic pain), encephalopathysecondary to a medical condition (including hepatic encephalopathy andanti-NMDA receptor encephalitis), seizure disorder (including statusepilepticus and monogenic forms of epilepsy such as Dravet's disease),stroke, traumatic brain injury, movement disorder (includingHuntington's disease and Parkinson's disease), vision impairment,hearing loss, or tinnitus.

In some embodiments, the disorder is sterol synthesis disorder.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein (e.g., a compound of Formula (III), (II), or(I)) are deuterium-enriched.

Deuterium (D or ²H) is a stable, non-radioactive isotope of hydrogen andhas an atomic weight of 2.0144. Hydrogen naturally occurs as a mixtureof the isotopes ¹H (hydrogen or protium), D (²H or deuterium), and T (³Hor tritium). The natural abundance of deuterium is 0.015%. One ofordinary skill in the art recognizes that in all chemical compounds witha H atom, the H atom actually represents a mixture of H and D, withabout 0.015% being D. Thus, compounds with a level of deuterium that hasbeen enriched to be greater than its natural abundance of 0.015% shouldbe considered unnatural and, as a result, novel over their non-enrichedcounterparts.

The effects of deuterium modification on a compound's metabolicproperties are not predictable, even when deuterium atoms areincorporated at known sites of metabolism. Only by actually preparingand testing a deuterated compound can one determine if and how the rateof metabolism will differ from that of its non-deuterated counterpart.See, for example, Fukuto et al. (J. Med. Chem. 1991, 34, 2871-76). Manycompounds have multiple sites where metabolism is possible. The site(s)where deuterium substitution is required and the extent of deuterationnecessary to see an effect on metabolism, if any, will be different foreach compound.

Unless otherwise stated, when a position is designated specifically as“H” or “hydrogen,” the position is understood to have hydrogen at itsnatural abundance isotopic composition. Also unless otherwise stated,when a position is designated specifically as “D” or “deuterium,” theposition is understood to have deuterium at an abundance that is atleast 3000 times greater than the natural abundance of deuterium, whichis 0.015% (i.e., the term“D” or “deuterium” indicates at least 45%incorporation of deuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance of an element at the specified positionin a compound of this invention and the naturally occurring abundance ofthat isotope.

Increasing the amount of deuterium present in a compound (e.g., acompound of Formula (I) is called “deuterium-enrichment,” and suchcompounds are referred to as “deuterium-enriched” compounds. If notspecifically noted, the percentage of enrichment refers to thepercentage of deuterium present in the compound.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each deuterium present at a site designated at apotential site of deuteration on the compound of at least 3500 (52.5.%deuterium incorporation), at least 4000 (60% deuterium incorporation),at least 4500 (67.5% deuterium incorporation), at least 5000 (75%deuterium incorporation), at least 5500 (82.5% deuterium incorporation),at least 6000 (90% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6633.3 (99.5% deuteriumincorporation). It is understood that the isotopic enrichment factor ofeach deuterium present at a site designated as a site of deuteration isindependent of other deuterated sites. For example, if there are twosites of deuteration on a compound one site could be deuterated at 52.5%while the other could be deuterated at 75%. The resulting compound wouldbe considered to be a compound wherein the isotopic enrichment factor isat least 3500 (52.5%).

Because the natural abundance of deuterium is about 0.015%,approximately one in every 6,667 naturally occurring compounds ofFormula (III), e.g., a compound of Formula (I) or (II), would beexpected to have one naturally occurring compound of Formula (II), e.g.,a compound of Formula (I) or (II), with one deuterium present.

In some embodiments, the compounds of Formula (III) comprise an amountof deuterium-enrichment that is more than the amount ofdeuterium-enrichment present in naturally occurring compounds of Formula(III).

All percentages given for the amount of deuterium present are molepercentages.

It can be difficult in the laboratory to achieve 100% deuteration at anyone site of a lab scale amount of compound (e.g., milligram or greater).When 100% deuteration is recited or a deuterium atom is specificallyshown in a structure, it is assumed that a small percentage of hydrogenmay still be present. Deuterium-enriched can be achieved by eitherexchanging protons with deuterium or by synthesizing the molecule withenriched starting materials.

Also described herein is the isolation or purification ofdeuterium-enriched compounds of Formula (III), e.g., a compound ofFormula (I) or (II)). The isolated or purified deuterium-enrichedcompounds of Formula (III), e.g., a compound of Formula (I) or (II) areabove the naturally occurring levels.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

The articles “a” and “an” may be used herein to refer to one or to morethan one (i.e. at least one) of the grammatical objects of the article.By way of example “an analogue” means one analogue or more than oneanalogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In someembodiments, an alkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). Insome embodiments, an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”).In some embodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”).Unless otherwise specified, each instance of an alkyl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted alkyl”) or substituted (a “substituted alkyl”) with oneor more substituents; e.g., for instance from 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₄ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₄ alkyl. Common alkyl abbreviations include Me (—CH₃), Et(—CH₂CH₃), or iPr (—CH(CH₃)₂).

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻,Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, sulfonate ions(e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate,benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate,naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonicacid-2-sulfonate, and the like), and carboxylate ions (e.g., acetate,ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, and the like).

These and other exemplary substituents are described in more detail inthe Detailed Description, and Claims. The invention is not intended tobe limited in any manner by the above exemplary listing of substituents.

Other Definitions

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Hydroxy” refers to the radical —OH.

Alkyl groups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl group). In general, the term“substituted”, whether preceded by the term “optionally” or not, meansthat at least one hydrogen present on a group (e.g., a carbon ornitrogen atom) is replaced with a permissible substituent, e.g., asubstituent which upon substitution results in a stable compound, e.g.,a compound which does not spontaneously undergo transformation such asby rearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group has a substituent at one ormore substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. The term “substituted” iscontemplated to include substitution with all permissible substituentsof organic compounds, any of the substituents described herein thatresults in the formation of a stable compound. The present inventioncontemplates any and all such combinations in order to arrive at astable compound. For purposes of this invention, heteroatoms such asnitrogen may have hydrogen substituents and/or any suitable substituentas described herein which satisfy the valencies of the heteroatoms andresults in the formation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb) SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃ , —OSi(R^(aa))₃,—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa), —SC(═S)SR^(aa),—SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa), —SC (═O)R^(aa),—P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂, —OP(═O)₂N(R^(bb))₂,—P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂, —P(R^(cc))₃, —OP(R^(cc))₂,—OP(R^(cc))₃, —B(R^(aa))₂, —B (OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with 0,1, 2, 3, 4, or 5 R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc),

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0,1,2,3,4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0,1,2,3,4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0,1,2,3,4, or 5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃ ⁺X⁻,—N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH, —SC₁₋₆alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆ alkyl),—OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆ alkyl)₂,—OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)C(═O)(C₁₋₆alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂, —NHC(═O)NH(C₁₋₆alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆ alkyl),—OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆ alkyl),—C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl), —OC(NH)NH₂,—NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl), —SO₂N(C₁₋₆alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl, —SO₂OC₁₋₆ alkyl,—OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃, —OSi(C₁₋₆alkyl)₃—C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂, —C(═O)S(C₁₋₆alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆ alkyl),—P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆ alkyl)₂, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or twogeminal R^(gg) substituents can be joined to form ═O or ═S; wherein X⁻is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻,I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), −P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(cc) groups attached to a nitrogenatom are joined to form a 3-14 membered heterocyclyl or 5-14 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,heterocyclyl, aryl, and heteroaryl is independently substituted with0,1,2,3,4, or 5 R ^(dd) groups, and wherein R are as defined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁻(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

As generally described herein, the present invention provides oxysterolsuseful for preventing and/or treating a broad range of disorders,including, but not limited to, NMDA— mediated disorders. These compoundsare expected to show improved in vivo potency, pharmacokinetic (PK)properties, oral bioavailability, formulatability, stability, and/orsafety as compared to other oxysterols.

Compounds

In one aspect, provided herein are compounds according to Formula (III):

or a pharmaceutically acceptable salt thereof, wherein each of R² and R³is independently hydrogen or —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl); R⁵ isabsent or hydrogen; n is 1 or 2;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and at least one hydrogen is replacedwith a deuterium.

In one aspect, provided herein are compounds according to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen ordeuterium; each of R² and R³ is independently hydrogen, deuterium or—C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl); R⁴ is hydrogen or deuterium; R⁵ isabsent, hydrogen, or deuterium; n is 1 or 2;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and at least one of R¹, R², R³, R⁴,or R⁵ is deuterium.

In some embodiments, the compound of Formula (II) is a compound ofFormula (I):

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium.

In some embodiments, one of R² and R³ is deuterium and the other of R²and R³ is —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). In some embodiments, eachof R² and R³ is independently —C₁₋₆ alkyl (e.g., C₁₋₆ haloalkyl). Insome embodiments, each of R² and R³ is independently isopropyl, —CH₃, or—CF₃.

In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ isdeuterium.

In some embodiments,

represents a single bond. In some embodiments, R⁵ is hydrogen. In someembodiments, R⁵ is deuterium.

In some embodiments,

represents a double bond and R⁵ is absent.

In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-A):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium.

In some embodiments, one of R² and R³ is deuterium and the other of R²and R³ is —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). In some embodiments, eachof R² and R³ is independently —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). Insome embodiments, each of R² and R³ is independently isopropyl, —CH₃, or—CF₃.

In some embodiments,

represents a single bond. In some embodiments, R⁵ is hydrogen. In someembodiments, R⁵ is deuterium.

In some embodiments,

represents a double bond and R⁵ is absent.

In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-B):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is hydrogen. In some embodiments, R² isdeuterium.

In some embodiments, one of R² and R³ is deuterium and the other of R²and R³ is —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). In some embodiments, eachof R² and R³ is independently —C₁₋₆ alkyl (e.g., —C₁₋₆haloalkyl). Insome embodiments, each of R² and R³ is independently isopropyl, —CH₃, or—CF₃.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I—C):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium.

In some embodiments, one of R² and R³ is deuterium and the other of R²and R³ is —C₁₋₆ alkyl (e.g., —C₁₋₆haloalkyl). In some embodiments, eachof R² and R³ is independently —C₁₋₆ alkyl (e.g., —C₁₋₆haloalkyl). Insome embodiments, each of R² and R³ is independently isopropyl, —CH₃, or—CF_(3.)

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-D):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium.

In some embodiments, one of R² and R³ is deuterium and the other of R²and R³ is —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). In some embodiments, eachof R² and R³ is independently —C₁₋₆ alkyl (e.g., —C₁₋₆ haloalkyl). Insome embodiments, each of R² and R³ is independently isopropyl, —CH₃, or—CF₃.

In some embodiments, the compound of Formula (I) is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and an effective amountof a compound of Formula (III).

When employed as pharmaceuticals, the compounds provided herein aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, thecarrier is a parenteral carrier, oral or topical carrier.

The present invention also relates to a compound of Formula (III) orpharmaceutical composition thereof for use as a pharmaceutical or amedicament.

Generally, the compounds provided herein are administered in atherapeutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions provided herein can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds provided herein are preferablyformulated as either injectable or oral compositions or as salves, aslotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The above-described components for orally administrable, injectable, ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's The Science and Practice of Pharmacy, 21stedition, 2005, Publisher: Lippincott Williams & Wilkins, which isincorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of Formula (III). In one embodiment, theformulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-l, 4-linkedglucose units, respectively, optionally comprising one or moresubstituents on the linked sugar moieties, which include, but are notlimited to, methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl etherβ-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, theformulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of Formula (III). The acid which may beused to prepare the pharmaceutically acceptable salt is that which formsa non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 240-270 mg tablets (80-90 mg of active compound per tablet)in a tablet press.

Exemplary Formulation 2—Capsules: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a starch diluent in an approximate 1:1 weight ratio. The mixture isfilled into 250 mg capsules (125 mg of active compound per capsule).

Exemplary Formulation 3—Liquid: A compound of Formula (III), orpharmaceutically acceptable salt thereof, (125 mg) may be admixed withsucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may beblended, passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color are diluted with water and added with stirring.Sufficient water may then be added to produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 450-900 mg tablets (150-300 mg of active compound) in atablet press.

Exemplary Formulation 5—Injection: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be dissolved or suspendedin a buffered sterile saline injectable aqueous medium to aconcentration of approximately 5 mg/mL.

Exemplary Formulation 6—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 90-150 mg tablets (30-50 mg of active compound per tablet)in a tablet press.

Exemplary Formulation 7—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be may be admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ratio. Aminor amount of magnesium stearate is added as a lubricant. The mixtureis formed into 30-90 mg tablets (10-30 mg of active compound per tablet)in a tablet press.

Exemplary Formulation 8—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet)in a tablet press.

Exemplary Formulation 9—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 150-240 mg tablets (50-80 mg of active compound per tablet)in a tablet press.

Exemplary Formulation 10—Tablets: A compound of Formula (III), orpharmaceutically acceptable salt thereof, may be admixed as a dry powderwith a dry gelatin binder in an approximate 1:2 weight ratio. A minoramount of magnesium stearate is added as a lubricant. The mixture isformed into 270-450 mg tablets (90-150 mg of active compound per tablet)in a tablet press.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions the regimenfor treatment usually stretches over many months or years so oral dosingis preferred for patient convenience and tolerance. With oral dosing,one to five and especially two to four and typically three oral dosesper day are representative regimens. Using these dosing patterns, eachdose provides from about 0.01 to about 20 mg/kg of the compound providedherein, with preferred doses each providing from about 0.1 to about 10mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

Methods of Treatment and Use

Compounds of the present invention, e.g., a compound of Formula (III),and pharmaceutically acceptable salts thereof, as described herein, aregenerally designed to modulate NMDA function, and therefore to act asoxysterols for the treatment and prevention of, e.g., CNS-relatedconditions in a subject. In some embodiments, the compounds describedherein, e.g., a compound of Formula (III), and pharmaceuticallyacceptable salts thereof, as described herein, are generally designed topenetrate the blood brain barrier (e.g., designed to be transportedacross the blood brain barrier). Modulation, as used herein, refers to,for example, the inhibition or potentiation of NMDA receptor function.In certain embodiments, the compound of Formula (III), orpharmaceutically acceptable salt thereof, may act as a negativeallosteric modulator (NAM) of NMDA, and inhibit NMDA receptor function.In certain embodiments, the present invention, e.g., a compound ofFormula (III), or pharmaceutically acceptable salt thereof, may act aspositive allosteric modulators (PAM) of NMDA, and potentiate NMDAreceptor function. In certain embodiments, the compound of Formula(III), or pharmaceutically acceptable salt thereof, modulates NMDAfunction, but does not act as a negative allosteric modulator (NAM) orpositive allosteric modulator (PAM) of NMDA.

In some embodiments, the disorder is cancer. In some embodiments, thedisorder is diabetes. In some embodiments, the disorder is a sterolsynthesis disorder. In some embodiments, the disorder is agastrointestinal (GI) disorder, e.g., constipation, irritable bowelsyndrome (IBS), inflammatory bowel disease (IBD) (e.g., ulcerativecolitis, Crohn's disease), structural disorders affecting the GI, analdisorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, colitis. In some embodiments, the disorder isinflammatory bowel disease.

In some embodiments, the disorder is Smith-Lemli—Opitz Syndrome (SLOS).In some embodiments, the disorder is desmosterolosis. In someembodiments, the disorder is sitosterolemia. In some embodiments, thedisorder is cerebrotendinous xanthomatosis (CTX). In some embodiments,the disorder is Mevalonate Kinase Deficiency (MKD). In some embodiments,the disorder is SC₄MOL gene mutation (SMO Deficiency). In someembodiments, the disorder is Niemann-Pick disease. In some embodiments,the disorder is autism spectrum disorder (ASD). In some embodiments, thedisorder is associated with phenylketomuria.

Exemplary conditions related to NMDA-modulation includes, but are notlimited to, gastrointestinal (GI) disorder, e.g., constipation,irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) (e.g.,ulcerative colitis, Crohn's disease), structural disorders affecting theGI, anal disorders (e.g., hemorrhoids, internal hemorrhoids, externalhemorrhoids, anal fissures, perianal abscesses, anal fistula), colonpolyps, cancer, colitis, and CNS conditions, e.g., as described herein.

Exemplary CNS conditions related to NMDA-modulation include, but are notlimited to, adjustment disorders, anxiety disorders (includingobsessive-compulsive disorder, posttraumatic stress disorder, socialphobia, generalized anxiety disorder), cognitive disorders (includingAlzheimer's disease and other forms of dementia), dissociativedisorders, eating disorders, mood disorders (including depression (e.g.,postpartum depression), bipolar disorder, dysthymic disorder,suicidality), schizophrenia or other psychotic disorders (includingschizoaffective disorder), sleep disorders (including insomnia),substance abuse-related disorders, personality disorders (includingobsessive-compulsive personality disorder), autism spectrum disorders(including those involving mutations to the Shank group of proteins(e.g., Shank3)), neurodevelopmental disorders (including Rett syndrome),multiple sclerosis, sterol synthesis disorders, pain (including acuteand chronic pain), seizure disorders (including status epilepticus andmonogenic forms of epilepsy such as Dravet's disease, and TuberousSclerosis Complex (TSC)), stroke, traumatic brain injury, movementdisorders (including Huntington's disease and Parkinson's disease) andtinnitus. In certain embodiments, the compound of the present invention,e.g., a compound of Formula (III), or pharmaceutically acceptable saltthereof, can be used to induce sedation or anesthesia. In certainembodiments, the compound of Formula (III), or pharmaceuticallyacceptable salt thereof, is useful in the treatment or prevention ofadjustment disorders, anxiety disorders, cognitive disorders,dissociative disorders, eating disorders, mood disorders, schizophreniaor other psychotic disorders, sleep disorders, substance-relateddisorders, personality disorders, autism spectrum disorders,neurodevelopmental disorders, sterol synthesis disorders, pain, seizuredisorders, stroke, traumatic brain injury, movement disorders and visionimpairment, hearing loss, or tinnitus.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of the present invention,e.g., a compound of Formula (III), or a pharmaceutically acceptable saltthereof.

In yet another aspect, the present invention provides a combination of acompound of the present invention, e.g., a compound of Formula (III), orpharmaceutically acceptable salt thereof, and another pharmacologicallyactive agent. The compounds provided herein can be administered as thesole active agent or they can be administered in combination with otheragents. Administration in combination can proceed by any techniqueapparent to those of skill in the art including, for example, separate,sequential, concurrent and alternating administration.

Diseases and Disorders

Described herein are methods of treating a sterol synthesis disorder.Exemplary disorders are described herein. The methods includeadministering to a subject, e.g., a subject suffering from a sterolsynthesis disorder such as SLOS, a NMDA receptor modulating compound.Exemplary compounds are described herein.

Sterol Synthesis Disorders

In one aspect, described herein are methods for treating a sterolsynthesis disorder. Cholesterol has an essential rule in growth anddevelopment. It is a membrance lipid and a precursor to many moleculesthat play important roles in cellular growth and differentiation,protein glycosylation, and signaling pathways. Biosynthesis ofcholesterol involves a number of enzymes and intermediates. Disordersresulting from a deficiency in any of the enzymes involved incholesterol biosynthesis lead to the accumulation of intermediates andimbalance in biomolecules, resulting in disorders including congenitalskeletal malformations, dysmorphic facial features, psychomotorretardation, and failure to thrive. In an embodiment, a sterol synthesisdisorder or symptom of a sterol synthesis disorder can be treated byadministering to a subject suffering from a sterol synthesis disorder acompound described herein, such as a NMDA receptor modulating compoundas described herein. Additional disorders are described below.

Smith-Lemli-Opitz Syndrome

In one aspect, described herein are methods for treatingSmith-Lemli-Opitz Syndrome (or SLOS, or 7-dehydrocholesterol reductasedeficiency). SLOS is an inborn error of cholesterol synthesis. Inaddition to microcephaly, moderate to severe intellectual disability,sensory hypersensitivity, stereotyped behaviors, dysmorphic facialfeatures, and syndactyly of the second/third toes, a feature of thedisease is reduced cerebrosterol (24(S)-hydroxycholesterol) levels. SLOSis an autosomal recessive genetic condition resulting from deficiency inthe final enzyme of the cholesterol synthesis pathway, and causes low orlow-normal plasma cholesterol levels and increased 7- and8-dehydrocholesterol (DHC; 7DHC and 8DHC) levels. Common therapiescurrently used include dietary cholesterol supplementation, treatmentwith 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoAreductase inhibitors, also known as statins), and treatment with agentsthat enhance cholesterol production and/or accretion; and to decreasethe accumulation of 7DHC and 8DHC, the potentially toxic precursors ofcholesterol.

Desmosterolosis

Desmosterolosis is a deficiency in desmosterol reductase and has asimilar phenotype to SLOS. In one aspect, described herein are methodsfor treating desmosterolosis with compounds described herein.

Sitosterolemia

Sitosterolemia is a rare autosomal recessive disorder caused bymutations in two ATP-binding cassette (ABC) transporter genes (ABCG5 andABCG8). Sitosterolemia enhances the absorption of plant sterols andcholesterol from the intestines. Patients typically present with tendonand tuberous xanthomas and premature coronary artery disease. In oneaspect, described herein are methods for treating sitosterolemia withcompounds described herein.

Cerebrotendinous Xanthomatosis (CTX)

In one aspect, described herein are methods for treatingcerebrotendinous xanthomatosis (also referred to as cerebralcholesterosis, or Van Bogaert-Scherer-Epstein syndrome) with compoundsdescribed herein. CTX can be caused by a mutation in the CYP27A1 gene,which produces the sterol 27-hydroxylase enzyme. Sterol 27-hydroxylasemetabolizes cholesterol into bile acids (e.g., chenodeoxycholic acid)that are important in the absorption of fats in the intestine. Enzymedysfunction can lead to cholesterol accumulation in tissues. CTX ischaracterized by childhood diarrhea, cataracts, tendon xanthomas,reduced mental capability and abnormal movements in adults.

Mevalonate Kinase Deficiency Syndromes (MKD)

Mevalonate Kinase Deficiency (also referred to as mevalonic aciduria (amore severe form of MKD), or Hyper IgD Syndrome (HIDS, orhyperimmunoglobulinemia D) with period fever syndrome (a more benignform of MKD)) causes an accumulation of mevalonic acid in the urine as aresult of insufficient activity of mevalonate kinase. MKD can result indevelopmental delay, hypotonia, anemia, hepatosplenomegaly, dysmorphicfeatures, mental retardation, and overall failure to thrive. Mevalonicaciduria is characterized by delayed physical and mental development,failure to thrive, recurrent episodes of fever with vomiting anddiarrhea, enlarged liver, spleen and lymph nodes, microcephaly (smallhead size), cataract, low muscle tone, short statute, distinct facialfeatures, ataxia, and anemia. HIDS is characterized by recurrentepisodes of fever associated with swollen lymph nodes, joint pain,gastrointestinal issues and skin rash. In one aspect, described hereinare methods for treating MKD with the compounds described herein.

SC4MOL Gene Mutation (SMO Deficiency)

SC4MOL gene deficiency is a genetic disorder in the cholesterolbiosynthesis pathway (e.g., mutations in the SC4MOL gene encoding anovel sterol oxidase). SC4MOL deficiency is characterized by theaccumulation of dimethyl and monomethyl sterols that can be detected inblood, skin flakes or primary skin fibroblasts. In one aspect, describedherein are methods for treating SMO deficiency with compounds describedherein.

Niemann-Pick Disease

Niemann-Pick disease is a lysosomal storage disease resulting from agenetic mutation that affects metabolism. Niemann-Pick disease leads toabnormal accumulation of cholesterol and other fatty substances (lipids)due to an inability of the body to transport the substances. Theaccumulation damages the affected areas.

Autism

In one aspect, described herein are methods for treating autism spectrumdisorder or autism. Autism spectrum disorder (ASD) and autism refer to agroup of complex disorders of brain development. Autism is typicallycharacterized by difficulties in social interaction, for example inverbal and nonverbal communication. Repetitive behaviors are also oftenseen in indidividuals having autism. Autism can be associated withintellectual disability, difficulties in motor coordination andattention and physical health issues, e.g., sleep and gastrointestinaldisturbances. Individuals having autism can also excel in visual skills,music, math and art. Autism can refer to autistic disorder, childhooddisintegrative disorder, pervasive developmental disorder-not otherwisespecified (PDD-NOS), and Asperger syndrome. Autism also refers tomonogenetic causes of autism such as synaptophathy's, e.g., Rettsyndrome, Fragile X syndrome, Angelman syndrome.

Disorders Associated with Phenylketonuria

In one aspect, described herein are methods for treating disordersassociated with phenylketonuria (e.g., cognitive disorders) withcompounds described herein. Phenylketonuria can lead tohypochesterolemia and lowered vitamin D status. Total and low-densitycholesterols and 25-hydroxy vitamin D have been found to be decreased insubjects suffering from phenylketonuria as compared with subjects notsuffering from phenylketonuria (Clin. Chim. Acta 2013, 416: 54-59).24S-hydroxycholesterol and 27S-hydroxycholesterol and7α-hydroxycholesterol (e.g., representing peripheral and hepaticcholesterol elimination, respectively) have been shown to besignificantly decreased in subjects suffering from phenylketonuria,while 7β-hydroxycholesterol (e.g., reflecting oxidative stress) wasincreased significantly in subjects suffering from phenylketonuria.Changes in the levels of 24S-OHC and 7β-hydroxycholesterol correlatewith phenylalanine level, and 27S-hydroxycholesterol levels maycorrelate with the 25-hydroxy vitamin D level in subjects suffering fromphenylketonuria.

Alternative Embodiments

In an alternative embodiment, compounds described herein may alsocomprise one or more isotopic substitutions other than the substitutionof ¹H with deuterium. For example, hydrogen may also be ³H (T ortritium); carbon may be, for example, ¹³C or ¹⁴C; oxygen may be, forexample, ¹⁸O; nitrogen may be, for example, ¹⁵N, and the like. In otherembodiments, a particular isoptope (e.g., ³H, ¹³C, ¹⁴C, ¹⁸O, or ¹⁵N) canrepresent at least 1%, at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 99%, or at least 99.9% of the total isotopic abundance of anelement that occupies a specific site of the compound.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Example 1 Synthesis of Compounds 1, 2, and 3

Synthesis of Compound A-2. To a solution of A-1 (1 g, 2.48 mmol) in DCM(50 mL) was added DMP (2.31 g, 5.45 mmol) at 20° C. The mixture wasstirred at 20° C. for 30 mins, followed by the addition of water (20 mL)and NaHCO₃ (2 g, solid). The mixture was filtered, and the organic phasewas separated, washed with saturated Na₂S₂O₃ (50 mL), dried over Na₂SO₄,filtered, and concentrated under vacuum to give a residue that waspurified by column chromatography on silica gel (PE:EtOAc=100:1 to 20:1)to afford A-2 (180 mg, 18%) as an off-white solid. ¹H NMR (400 MHz,CDCl₃) δ5.40-5.30 (m, 1H), 3.60-3.45 (m, 1H), 2.65-2.15 (m, 5H),2.05-1.60 (m, 6H), 1.55-1.85 (m, 30H), 0.67 (s, 1H).

Synthesis of Compound 1. To a solution of A-2 (180 mg, 0.45 mmol) inMeOH (15 mL) was added NaBD₄ (93.7 mg, 2.24 mmol) at 20° C. The mixturewas stirred at 20° C. for 3 mins, then quenched with sat. NH₄Cl (20 mL).The solvent was evaporated to ½ volume under vacuum, and the mixture wasextracted with DCM (3×20 mL). The combined organic layers were washedwith brine (2×50 mL), dried over Na₂SO₄, filtered, and concentratedunder vacuum to give a crude product, which was triturated from PE (10mL) to give Compound 1 (130 mg, 72%). ¹H NMR (400 MHz, CDCl₃) δ5.40-5.30(m, 1H), 3.60-3.45 (m, 1H), 2.35-2.10 (m, 2H), 2.10-1.70 (m, 5H),1.65-1.59 (m, 3H), 1.55-0.70 (m, 30H), 0.68 (s, 3H). LCMS Rt=1.265 minin 2 min chromatography, MS ESI calcd. for C₂₇H₄₄DO [M+H−H₂O]⁺ 386,found 386. HRMS MS ESI calcd. for C₂₇H₄₅DNaO₂ [M+Na]⁺ 426.3453, found426.3454.

Synthesis of Compounds 2 and 3. Compound 1 (130 mg) was separated by SFCto give Compound 2 (11.5 mg, 11%, D-ratio: 97%) and Compound 3 (19.4 mg,19%, D-ratio: 98%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃)δ5.40-5.30 (m, 1H), 3.52 (m, 1H), 2.34-2.18 (m, 2H), 2.05-1.93 (m, 2H),1.89-1.78 (m, 3H), 1.72-1.57 (m, 3H), 1.55-0.86 (m, 30H), 0.68 (s, 3H).LCMS Rt=1.210 min in 2 min chromatography, MS ESI calcd. for C₂₇H₄₄DO[M+H−H₂O]⁺ 386, found 386. HRMS MS ESI calcd. for C₂₇H₄₄DO [M+H−H₂O]⁺386.3528, found 386.3520.

Example 2 Synthesis of Compound 4

Synthesis of A-4: To a solution of A-3 (1.0 g, 2.48 mmol) in DCM (20 mL)was added DMP (2.10 g, 4.96 mmol) at 0° C. The mixture was stirred at25° C. for 0.5 h, then quenched with saturated NaHCO₃/Na₂S₂O₃=1:3 (15mL) and extracted with CH₂Cl₂ (2×50 mL). The organic phase was washedwith brine (50 mL), dried over Na₂SO₄, and concentrated. The residue waspurified by column chromatography on silica gel (PE/EtOAc=50/1) toafford A-4 (600 mg, 60%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃)δ5.34-5.29 (m, 1H), 3.66 (s, 3H), 3.29-3.26 (m, 1H), 2.84-2.83 (m, 1H),2.50-1.57 (m, 10H), 1.54-1.20 (m, 10H), 1.18 (s, 3H), 1.17-0.67 (m, 8H),0.54 (s, 3H).

Synthesis of A-5: To a solution of A-4 (548 mg, 1.37 mmol) in MeOH (5mL) was added NaBD₄ (69.3 mg, 1.65 mmol) at 20° C. The mixture wasstirred at 20° C. for 30 mins, then quenched with saturated NH₄Cl (15mL) and extracted with EtOAc (2×20 mL). The organic phase was washedwith brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by column chromatography on silica gel(PE/EtOAc=15/1) to afford A-5 (290 mg, 52%) as an off-white solid. ¹HNMR (400 MHz, CDCl₃) δ5.35-5.34 (m, 1H), 3.66 (s, 3H), 2.30-2.23 (m,4H), 2.05-1.57 (m, 10H), 1.53-0.92 (m, 20H), 0.67 (s, 3H).

Synthesis of Compound 4: To a solution of A-5 (250 mg, 619 μmol in THF(3 mL) was added MeLi (1.93 mL, 3.09 mmol) at 0° C. under N₂. Themixture was stirred at 20° C. for 12 hrs, then quenched with saturatedNH₄Cl (5 mL) at 0° C. The mixture was treated with water (30 mL) andextracted with EtOAc (2×20 mL). The organic phase was washed with brine(30 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel (PE/EtOAc=3/1) to affordCompound 4 (131.8 mg, 53%, deuterated ratio: 97%) as an off-white solid.¹H NMR (400 MHz, CDCl₃) δ5.35-5.34 (m, 1H), 2.30-2.27 (m, 2H), 1.99-1.81(m, 5H), 1.55-1.27 (m, 11H), 1.25-0.92 (m, 23H), 0.64 (s, 3H). LCMSRt=1.425 min in 2.0 min chromatography, MS ESI calcd. for C₂₇H₄₂D[M+H−2H₂O]⁺ 368, found 368. HRMS MS ESI calcd. for C₂₇H₄₂D [M+H−2H₂O]⁺368.3422, found 368.3405.

Example 3 Synthesis of Compounds 5 and 6

Synthesis of A-6: To a solution of A-1 (500 mg, 1.24 mmol) in DCM (20mL) was added DMP (5.21 g, 12.3 mmol) at 20° C. The mixture was stirredat 20° C. for 30 mins, then water (10 mL) was added, followed by theaddition of NaHCO₃ (10 g). The mixture was filtered, and the organicphase was separated, washed with saturated Na₂S₂O₃ (100 mL), dried overNa₂SO₄, filtered, concentrated under vacuum and purified by columnchromatography on silica gel (PE:EtOAc=100:1 to 50:1) to give A-6 (230mg, 46%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ5.40-5.30 (m,1H), 3.35-3.20 (m, 1H), 2.90-2.75 (m, 1H), 2.65-2.20 (m, 6H), 2.10-1.60(m, 5H), 1.55-0.90 (m, 25H), 0.71 (s, 3H).

Synthesis of A-7: To a solution of A-6 (230 mg) in MeOH (10 mL) wasadded NaBD₄ (2.88 mg, 120 mmol) at 20° C. The mixture was stirred at 20°C. for 2 mins, at which point sat. NH₄Cl (20 mL) was added. The mixturewas concentrated in vacuum to ½ volume, then extracted with EtOAc (2×30mL), washed with brine (2×50 mL), dried over Na₂SO₄, filtered,concentrated under vacuum to give a crude product, which was purified bycolumn chromatography on silica gel (PE:EA=100:1 to 20:1) to give A-7(170 mg 42%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ5.40-5.30(m, 1H), 2.35-2.10 (m, 2H), 2.10-1.70 (m, 6H), 1.65-1.59 (m, 2H),1.55-0.70 (m, 30H), 0.68 (s, 3H).

Synthesis of Compounds 5 and 6: A-7 (170 mg) was separated by SFC togive Compound 5 (34 mg, 21%, D-ratio: 99%) as an off-white solid andCompound 6 (45.8 mg, 28%, D-ratio: 99.9%) as an off-white solids.Compound 5: ¹H NMR (400 MHz, CDCl₃) δ5.40-5.30 (m, 1H), 2.33-2.19 (m,2H), 2.05-1.93 (m, 2H), 1.90-1.78 (m, 3H), 1.71-1.60 (m, 2H), 1.55-0.85(m, 31H), 0.68 (s, 3H). LCMS Rt=1.196 min in 2 min chromatography, MSESI calcd. for C₂₇H₄₃D₂O [M+H−H₂O]⁺ 387, found 387. HRMS MS ESI calcd.for C₂₇H₄₄D₂NaO₂ [M+Na]⁺ 427.3516, found 427.3510. Compound 6: ¹H NMR(400 MHz, CDCl₃) δ5.40-5.30 (m, 1H), 2.32-2.19 (m, 2H), 2.05-1.92 (m,2H), 1.91-1.78 (m, 3H), 1.70-1.59 (m, 2H), 1.55-1.40 (m, 8H), 1.37-0.89(m, 23H), 0.68 (s, 3H). LCMS Rt=1.221 min in 2 min chromatography, MSESI calcd. for C₂₇H₄₃D₂O [M+H−H₂O]⁺ 387, found 387. HRMS MS ESI calcd.for C₂₇H₄₄D₂NaO₂ [M+Na]⁺ 427.3516, found 427.3511.

Example 4 Synthesis of Compound 7

Synthesis of A-17: To a solution of A-7 (330 mg, 0.8 mmol) in THF (20mL) was added benzoic acid (398 mg, 3.26 mmol) and PPh₃ (1.28 g, 4.89mmol) at 20° C. under N₂. The mixture was stirred at 20° C. for 20 mins,at which point DIAD (988 mg, 4.89 mmol) was added at 0° C. under N₂. Themixture was stirred at 0° C. for 20 mins, then warmed to 20° C. andstirred at 20° C. for 17 hrs. The mixture was quenched with water (30mL). The mixture was extracted with EtOAc (2×40 mL), washed with brine(2×80 mL), dried over Na₂SO₄, filtered and concentrated in vacuum togive A-17 (300 mg, crude), which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ8.15-7.95 (m, 4H),7.60-7.50 (m, 2H), 7.50-7.40 (m, 4H), 5.35-5.25 (m, 1H), 2.60-2.50 (m,1H), 2.40-2.30 (m, 1H), 2.10-0.80 (m, 34H), 0.75-0.50 (m, 5H).

Synthesis of Compound 7: To a solution A-17 (300 mg, 0.5 mmol) in THF (5mL) was added a solution of LiOH (100 mg, 4.17 mmol) in H₂O (2 mL) at10° C. MeOH (3 mL) was added, and the mixture was stirred at 40° C. for24 hrs. Water (10 mL) was then added, and the mixture was extracted withEtOAc (3×10 mL), washed with sat. NaHCO₃ (2×30 mL), brine (2×30 mL),dried over Na₂SO₄, filtered and concentrated under vacuum to give thecrude product (250 mg) as a yellow oil, which was purified by flashcolumn (0-30% EtOAc in PE, 50 min) to give Compound 7 (70 mg, 25%) as anoff-white solid. ¹H NMR (400 MHz, CDCl₃) δ5.50-5.35 (m, 1H), 2.60-2.50(m, 1H), 2.10-1.60 (m, 10H), 1.50-0.80 (m, 29H), 0.68 (s, 3H). LCMSRt=1.313 min in 2.0 min chromatography, 30-90 AB_E, purity 100%, MS ESIcalcd. for C₂₇H₄₃D₂O [M+H−H₂O]⁺ 387, found 387. HRMS MS ESI calcd. forC₂₇H₄₃D₂O [M+H−H₂O]⁺ 387.3590, found 387.3587.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures,for example, as described in WO 2013/036835 and WO 2014/160480. It willbe appreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, N.Y., 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative pyrazoles that have been listedherein. The compounds provided herein may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis. Exemplary chiral columns available for usein the separation/purification of the enantiomers/diastereomers providedherein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB,CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF,CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

¹H-NMR reported herein (e.g., for intermediates) may be a partialrepresentation of the full NMR spectrum of a compound, e.g., a compounddescribed herein. For example, the reported ¹H NMR may exclude theregion between δ (ppm) of about 1 to about 2.5 ppm. [0011] Exemplarygeneral method for preparative HPLC: Column: Waters RBridge prep 10 μmC18, 19*250 mm. Mobile phase: acetonitrile, water (NH₄HCO₃) (30 L water,24 g NH₄HCO₃, 30 mL NH₃.H₂O). Flow rate: 25 mL/min

Exemplary general method for analytical HPLC: Mobile phase: A: water (10mM NH₄HCO₃), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min Flowrate: 1.8 or 2 mL/min; Column: XBridge C18, 4.6*50mm, 3.5 μm at 45 C.

NMDA Potentiation

NMDA potentiation was assessed using either whole cell patch clamp ofmammalian cells which expressed NMDA receptors.

Whole-cell Patch Clamp of Mammalian Cells (Ionworks Barracuda (IWB))

-   The whole-cell patch-clamp technique was used to investigate the    effects of compounds on GlunN1/GluN2A glutamate receptors expressed    in mammalian cells. The results are shown on Table 1.-   HEK293 cells were transformed with adenovirus 5 DNA and transfected    with cDNA encoding the human GRIN1/GRIN2A genes. Stable    transfectants were selected using G418 and Zeocin-resistance genes    incorporated into the expression plasmid and selection pressure    maintained with G418 and Zeocin in the medium. Cells were cultured    in Dulbecco's Modified Eagle Medium/Nutrient Mixture (D-MEM/F-12)    supplemented with 10% fetal bovine serum, 100 μg/ml penicillin G    sodium, 100 μg/ml streptomycin sulphate, 100 μg/ml Zeocin, 5 μg/ml    blasticidin and 500 μg/ml G418.-   Test article effects were evaluated in 8-point    concentration-response format (4 replicate wells/concentration). All    test and control solutions contained 0.3% DMSO and 0.01% Kolliphor®    EL (C5135, Sigma). The test article formulations were loaded in a    384-well compound plate using an automated liquid handling system    (SciClone ALH3000, Caliper LifeScienses). The measurements were    perfomed using Ion Works Barracuda platform following this    procedure:-   Electrophysiological Procedures:    -   a) Intracellular solution (mM): 50 mM CsCl, 90 mM CsF, 2 mM        MgCl₂, 5 mM EGTA, 10 mM HEPES. Adjust to pH 7.2 with CsOH.    -   b) Extracellular solution, HB-PS (composition in mM): NaCl, 137;        KCl, 1.0; CaCl₂, 5; HEPES, 10; Glucose, 10; pH adjusted to 7.4        with NaOH (refrigerated until use).    -   c) Holding potential: −70 mV, potential during agonist/PAM        application: −40 mV.-   Recording procedure:    -   a) Extracellular buffer will be loaded into the PPC plate wells        (11 μL per well). Cell suspension will be pipetted into the        wells (9 μL per well) of the PPC planar electrode.

b) Whole-cell recording configuration will be established via patchperforation with membrane currents recorded by on-board patch clampamplifiers.

c) Two recordings (scans) will be performed. First, duringpre-application of test article alone (duration of pre-application −5min) and second, during test articles and agonist (EC₂₀ L-glutamate and30 μM glycine) co-application to detect positive modulatory effects ofthe test article.

-   Test Article Administration: The first pre-application will consist    of the addition of 20 μL of 2× concentrated test article solution    and, second, of 20 μL of 1× concentrated test article and agonist at    10 μL/s (2 second total application time).

TABLE 1 GluN2A PCA IWB Ephys Compound % potentiation at 3 μM 1 C 2 B 3 C4 A 5 C 6 D 7 C For Table 1, “A” indicates 10 to 75%, “B” indicatespotentiation of >75% to 150%; “C” indicates potentiation of >150% to225%; and “D” indicates potentiation of >225%.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub—range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1.-26. (canceled)
 27. A method of treating or preventing a CNS-relatedcondition comprising administering to a subject in need thereof aneffective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogenor deuterium; each of R² and R³ is independently deuterium or —Cl₁₋₆alkyl; R⁴ is hydrogen or deuterium; R⁵ is absent, hydrogen, ordeuterium; n is 1 or 2;

represents a single or double bond, wherein when one

is a double bond, the other

is a single bond and R⁵ is absent; and at least one of R¹, R², R³, R⁴,or R⁵ is deuterium.
 28. The method of claim 27, wherein the CNS-relatedcondition is selected from the group consisting of adjustment disorder,anxiety disorder, cognitive disorder, dissociative disorder, eatingdisorder, mood disorder, schizophrenia or other psychotic disorder,sleep disorder, substance-related disorder, personality disorder, autismspectrum disorders, neurodevelopmental disorder, multiple sclerosis,sterol synthesis disorders, pain, encephalopathy secondary to a medicalcondition, seizure disorder, stroke, traumatic brain injury, movementdisorder, vision impairment, hearing loss, or tinnitus.
 29. The methodaccording to claim 27, wherein: a. R¹ is hydrogen; or b. R¹ isdeuterium.
 30. The method according to claim 27, wherein R¹ isdeuterium.
 31. The method according to claim 27, wherein R¹ and R² aredeuterium.
 32. The method according to claim 27, wherein a. one of R²and R³ is deuterium and the other of R² and R³ is C₁₋₆ alkyl; or b. eachof R² and R³ is independently —C₁₋₆ alkyl.
 33. The method according toclaim 27, wherein each of R² and R³ is independently —C₁₋₆ alkyl. 34.The method according to claim 27, wherein each of R² and R³ isindependently isopropyl, —CH₃, or —CF₃.
 35. The method according toclaim 27, wherein R⁴ is hydrogen.
 36. The method according to claim 27,wherein: a. n is 1 b. n is 2
 37. The method according to claim 27,wherein n is
 2. 38. The method according to claim 27, wherein

represents a single bond.
 39. The method according to claim 27, whereinthe compound of Formula (I) is a compound of Formula (I-A):

or a pharmaceutically acceptable salt thereof.
 40. The method accordingto claim 27, wherein the compound of Formula (I) is a compound ofFormula (I-B):

or a pharmaceutically acceptable salt thereof.
 41. The method accordingto claim 27, wherein the compound of Formula (I) is a compound ofFormula (I-C):

or a pharmaceutically acceptable salt thereof.
 42. The method accordingto claim 27, wherein the compound of Formula (I) is a compound ofFormula (I-D):

or a pharmaceutically acceptable salt thereof.
 43. The method accordingto claim 27, wherein the compound of Formula (I) is selected from thegroup consisting of:


44. The method according to claim 27, wherein the compound of Formula(I) is a pharmaceutically acceptable salt of the compound selected fromthe group consisting of: